AChE enzymatic inhibition is a core focus of pharmacological intervention in Alzheimer's disease (AD). Yet, AChE has also been ascribed non‐hydrolytic functions, which seem related to its appearance ...in various isoforms. Neuronal AChE presents as a tailed form (AChE‐T) predominantly found on the neuronal synapse, and a facultatively expressed readthough form (AChE‐R), which exerts short to medium‐term protective effects. Notably, this latter form is also found in the periphery. While these non‐hydrolytic functions of AChE are most controversially discussed, there is evidence for them being additional targets of AChE inhibitors. This review aims to provide clarification as to the role of these AChE splice variants and their interplay with other cholinergic parameters and their being targets of AChE inhibition: AChE‐R is particularly involved in the mediation of (anti‐)apoptotic events in cholinergic cells, involving adaptation of various cholinergic parameters and a time‐dependent link to the expression of neuroprotective factors. The AChE‐T C‐terminus is central to AChE activity regulation, while isolated AChE‐T C‐terminal fragments mediate toxic effects via the α7 nicotinic acetylcholine receptor. There is direct evidence for roles of AChE‐T and AChE‐R in neurodegeneration and neuroprotection, with these roles involving AChE as a key modulator of the cholinergic system: in vivo data further encourages the use of AChE inhibitors in the treatment of neurodegenerative conditions such as AD since effects on both enzymatic activity and the enzyme's non‐hydrolytic functions can be postulated. It also suggests that novel AChE inhibitors should enhance protective AChE‐R, while avoiding the concomitant up‐regulation of AChE‐T.
In the cuprates, high-temperature superconductivity, spin-density-wave order, and charge-density-wave (CDW) order are intertwined, and symmetry determination is challenging due to domain formation. ...We investigated the CDW in the prototypical cuprate La_{1.88}Sr_{0.12}CuO_{4} via x-ray diffraction employing uniaxial pressure as a domain-selective stimulus to establish the unidirectional nature of the CDW unambiguously. A fivefold enhancement of the CDW amplitude is found when homogeneous superconductivity is partially suppressed by magnetic field. This field-induced state provides an ideal search environment for a putative pair-density-wave state.
Superconductivity often emerges in the proximity of, or in competition with, symmetry-breaking ground states such as antiferromagnetism or charge density waves15 (CDW). A number of materials in the ...cuprate family, which includes the high transition-temperature (high-Tc) superconductors, show spin and charge density wave order.
Pathobiology of neuropathic pain Zimmermann, Manfred
European Journal of Pharmacology,
10/2001, Volume:
429, Issue:
1
Book Review, Conference Proceeding, Journal Article
Peer reviewed
This review deals with physiological and biological mechanisms of neuropathic pain, that is, pain induced by injury or disease of the nervous system. Animal models of neuropathic pain mostly use ...injury to a peripheral nerve, therefore, our focus is on results from nerve injury models. To make sure that the nerve injury models are related to pain, the behavior was assessed of animals following nerve injury, i.e. partial/total nerve transection/ligation or chronic nerve constriction. The following behaviors observed in such animals are considered to indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters have been exploited to study the pharmacology and modulation of neuropathic pain. Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury. The mechanisms include unusual distributions of Na
+ channels, as well as abnormal responses to endogenous pain producing substances and cytokines such as tumor necrosis factor α (TNF-α). Persistent abnormal excitability of sensory nerve endings in a neuroma is considered a mechanism of stump pain after amputation. Any local nerve injury tends to spread to distant parts of the peripheral and central nervous system. This includes erratic mechano-sensitivity along the injured nerve including the cell bodies in the dorsal root ganglion (DRG) as well as ongoing activity in the dorsal horn. The spread of pathophysiology includes upregulation of nitric oxide synthase (NOS) in axotomized neurons, deafferentation hypersensitivity of spinal neurons following afferent cell death, long-term potentiation (LTP) of spinal synaptic transmission and attenuation of central pain inhibitory mechanisms. In particular, the efficacy of opioids at the spinal level is much decreased following nerve injury. Repeated or prolonged noxious stimulation and the persistent abnormal input following nerve injury activate a number of intracellular second messenger systems, implying phosphorylation by protein kinases, particularly protein kinase C (PKC). Intracellular signal cascades result in immediate early gene (IEG) induction which is considered as the ouverture of a widespread change in protein synthesis, a general basis for nervous system plasticity. Although these processes of increasing nervous system excitability may be considered as a strategy to compensate functional deficits following nerve injury, its by-product is widespread nervous system sensitization resulting in pain and hyperalgesia. An important sequela of nerve injury and other nervous system diseases such as virus attack is apoptosis of neurons in the peripheral and central nervous system. Apoptosis seems to induce neuronal sensitization and loss of inhibitory systems, and these irreversible processes might be in common to nervous system damage by brain trauma or ischemia as well as neuropathic pain. The cellular pathobiology including apoptosis suggests future strategies against neuropathic pain that emphasize preventive aspects.
The occurrence of strictures as a complication of Crohn's disease is a significant clinical problem. No specific antifibrotic therapies are available. This systematic review comprehensively addresses ...the pathogenesis, epidemiology, prediction, diagnosis and therapy of this disease complication. We also provide specific recommendations for clinical practice and summarise areas that require future investigation.
Abstract
The quantum Hall effect (QHE) is traditionally considered to be a purely two-dimensional (2D) phenomenon. Recently, however, a three-dimensional (3D) version of the QHE was reported in the ...Dirac semimetal ZrTe
5
. It was proposed to arise from a magnetic-field-driven Fermi surface instability, transforming the original 3D electron system into a stack of 2D sheets. Here, we report thermodynamic, spectroscopic, thermoelectric and charge transport measurements on such ZrTe
5
samples. The measured properties: magnetization, ultrasound propagation, scanning tunneling spectroscopy, and Raman spectroscopy, show no signatures of a Fermi surface instability, consistent with in-field single crystal X-ray diffraction. Instead, a direct comparison of the experimental data with linear response calculations based on an effective 3D Dirac Hamiltonian suggests that the quasi-quantization of the observed Hall response emerges from the interplay of the intrinsic properties of the ZrTe
5
electronic structure and its Dirac-type semi-metallic character.
The development of powerline communication (PLC) systems for Internet, voice, and data services requires measurement-based models of the transfer characteristics of the mains network suitable for ...performance analysis by simulation. This paper presents an analytic model describing complex transfer functions of typical powerline networks using only a small set of parameters. The model is based on physical signal propagation effects in mains networks including numerous branches and impedance mismatching. Besides multipath propagation accompanied by frequency-selective fading, signal attenuation of typical power cables increasing with length and frequency is considered. A verification of the model at a test network, as well as its use for definition of attenuation profiles and reference channels, demonstrate the practical value of the proposed model.
Charge density wave (CDW) order appears throughout the underdoped high-temperature cuprate superconductors, but the underlying symmetry breaking and the origin of the CDW remain unclear. We use X-ray ...diffraction to determine the microscopic structure of the CDWs in an archetypical cuprate YBa2Cu3O6.54 at its superconducting transition temperature ∼ 60 K. We find that the CDWs in this material break the mirror symmetry of the CuO2 bilayers. The ionic displacements in the CDWs have two components, which are perpendicular and parallel to the CuO2 planes, and are out of phase with each other. The planar oxygen atoms have the largest displacements, perpendicular to the CuO2 planes. Our results allow many electronic properties of the underdoped cuprates to be understood. For instance, the CDWs will lead to local variations in the electronic structure, giving an explicit explanation of density-wave states with broken symmetry observed in scanning tunnelling microscopy and soft X-ray measurements.
The application of magnetic fields to layered cuprates suppresses their high-temperature superconducting behaviour and reveals competing ground states. In widely studied underdoped YBa2Cu3O6+x ...(YBCO), the microscopic nature of field-induced electronic and structural changes at low temperatures remains unclear. Here we report an X-ray study of the high-field charge density wave (CDW) in YBCO. For hole dopings ∼0.123, we find that a field (B∼10 T) induces additional CDW correlations along the CuO chain (b-direction) only, leading to a three-dimensional (3D) ordered state along this direction at B∼15 T. The CDW signal along the a-direction is also enhanced by field, but does not develop an additional pattern of correlations. Magnetic field modifies the coupling between the CuO2 bilayers in the YBCO structure, and causes the sudden appearance of the 3D CDW order. The mirror symmetry of individual bilayers is broken by the CDW at low and high fields, allowing Fermi surface reconstruction, as recently suggested.
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